Polypeptide growth factors are a class of natural biological mediators that regulate the proliferation, differentiation, motility and matrix synthesis of nearly all cell types. These properties, demonstrable in vivo, have led to the proposal that such factors play important roles in soft and hard tissue repair. Platelet-derived growth factor (PDGF) is a well characterized example of such a polypeptide growth factor.
PDGF is a peptide hormone produced by blood platelets which influences the regulation of a broad array of biological systems including wound repair, arteriosclerosis, neoplasia, embryogenesis and bone marrow fibrosis. PDGF is a mitogen, that is, a substance which induces mitosis of cells and thus cellular proliferation. In wound repair, PDGF elicits both chemotactic and mitogenic responses in fibroblasts, smooth muscle, glial cells, etc. Injury to the endothelium lining the vessel wall is believed to cause platelets to adhere to exposed connective tissue at the wound site, with the concomitant release of PDGF. The released PDGF is thought to chemotactically recruit many cell types including fibroblasts, monocytes, glial and smooth muscle to migrate into the site of the wound. Increased proliferation of these cells leads to accelerated tissue regeneration and wound healing.
It has been demonstrated that the mitogenic properties of PDGF can be augmented by the addition of growth factors. For example, Antonaides et al. in U.S. Pat. Nos. 4,861,757 and 4,874,746 showed that a combination of PDGF and insulin-like growth factor-1 (IGF-1) or transforming growth factor alpha (TGF-.alpha.) had a greater effect on cell mitogenic activity than PDGF alone.
The effect of combining PDGF with other compounds is less clear. Levenson et al. in J. Biol. Chem.,260:8056-63 (1985), showed that the synthetic glucocorticoid, dexamethasone, acts synergistically with cartilage-derived growth factor (CDGF) to enhance the stimulation of DNA synthesis in quiescent Swiss 3T3 cells, while having only a neutral effect with PDGF. In addition, Levenson et al. showed that the addition of dexamethasone to PDGF-stimulated cultures had no effect on DNA synthesis over that observed with PDGF alone.